Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis – challenges and opportunities

Abstract

Important pharmacokinetic and -dynamic parameters for the drug discovery and development of new treatments for cutaneous leishmaniasis.

Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis

“…For the DNDI-0690 Klucel FFS, we also observed higher drug amounts in uninfected skin compared to infected skin in contrast to the higher concentrations extracted from the infected compared to healthy skin for the DNDI-0690 Eudragit FFS. This observation highlights the interaction between the physicochemical properties of the drug, the nature of the polymer, and the microenvironment of the parasite [32]. The hydrophobic DNDI-0690 permeates faster across the infected skin, which has been shown to be more permeable to both hydrophilic and hydrophobic drugs [33,34] but forms a smaller reservoir in infected skin, potentially due to the inflammation-associated oedema in the skin.…”

An old drug and different ways to treat cutaneous leishmaniasis: Intralesional and intramuscular meglumine antimoniate in a reference center, Rio de Janeiro, Brazil

“…Drugs with leishmanicidal properties when topically applied must be able to cross the corneal barrier of the skin, whose physicochemical properties hinder the penetration and local concentration of the drug. On the other side, drugs for IL treatment must penetrate in deeper layers of the dermis and reach parasitized macrophages, and the effectiveness of the treatment depends on this characteristic and the peculiarities of the infectious species [ 34 ].…”

Current leishmaniasis drug discovery

“…1,4 Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and manifests as a variety of cutaneous symptoms ranging from simple skin lesions and ulcers to disfiguring lesions on exposed parts of the body, leaving lifelong scars. 5 This form of the disease is not life threatening, unlike VL, but infected people are subjected to serious disability or stigma, leading to psychological damage and impaired access to employment, marriage, and education. 6,7 Most of the estimated 600 000 to one million new cases worldwide annually occur in the Mediterranean basin, the Middle East and Central Asia, and the Americas (Fig.…”

“…Another factor, especially for cutaneous leishmaniasis, is the belief that there is no great need for new drugs on the market because skin diseases are rarely fatal. 5,7 The discovery of a new drug is a long and expensive process, estimated to cost approximately 1.8 billion dollars and last 10-17 years. 35 In relation to the development of novel treatments for leishmaniasis, it is important to emphasize that the two main manifestations of the disease, VL and CL, although belonging to the same genus of parasite, differ substantially in the requirement of different pharmacokinetic profiles and compound formulations.…”

“…35 In relation to the development of novel treatments for leishmaniasis, it is important to emphasize that the two main manifestations of the disease, VL and CL, although belonging to the same genus of parasite, differ substantially in the requirement of different pharmacokinetic profiles and compound formulations. 5 Additionally, novel cutaneous antileishmanial drugs need to overcome a special feature of this disease: it is indispensable to pass through deeper vascularized dermis, other than most antibacterial and antifungal skin medicines that target avascular superficial layers of the skin. 5 Despite the factors that limit the interest of large pharmaceutical companies in the development of therapeutic…”